sVEGFR1 up-regulation via EGR1 impairs vascular repair in SFTSV-induced hemorrhage

Hemorrhage is a major pathological manifestation of certain viral infections, such as severe fever with thrombocytopenia syndrome (SFTS), Ebola, Crimean-Congo hemorrhagic fever and Dengue. SFTS is an emerging viral hemorrhagic fever caused by the SFTS virus (SFTSV). Hemorrhage and angiogenesis dysfunction are key manifestations of SFTSV infection but the underlying mechanisms remain unclear. Here, we demonstrate that SFTSV infection increases soluble vascular endothelial growth factor-receptor 1 (sVEGFR1) secretion from monocytes/macrophages. Increased sVEGFR1 in the serum of SFTS patients is positively correlated with disease severity. Moreover, we show that SFTSV induces sVEGFR1 upregulation via early growth response gene 1 (EGR1), of which VEGFR1 is a downstream target. Serum from SFTS patients containing high levels of sVEGFR1 inhibit angiogenesis, which can be reversed by removal of sVEGFR1. Treatment of SFTSV-infected animals with sVEGFR1 neutralizing antibodies improves angiogenesis and prevents blood vessel leaks in vivo. In conclusion, we show that SFTSV infection induces sVEGFR1 secretion through EGR1 upregulation, thereby contributing to hemorrhage.